Non-small cell lung cancer (NSCLC) is the most common lung cancer. Half of NSCLC shows WNT activation, marking poor survival. StemSynergy Therapeutics Inc (SSTI) has identified a family of WNT inhibitors based on a novel chemical scaffold, with our lead molecule (SST-215) demonstrating efficacy against WNT-driven colorectal cancer. In Phase I SBIR studies, many NSCLC cell lines were also exquisitely sensitive to SSTI compounds. Remarkably, SST-215 showed efficacy against both therapy-resistant cell lines derived from lung metastases, in KRAS mutant lung cancer lines, and in a patient-derived NSCLC xenograft model--a high bar for efficacy. Despite this promise, SST-215 is metabolized and accumulates to low levels in lung and brain (sites of NSCLC metastases). We propose to test derivatives of our lead molecule scaffold, many of which are already synthesized, to identify compounds with bioavailability and distribution characteristics optimized for the lung cancer, including the common sites of metastases. Potent compounds will be further stratified by absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Efficacy will be assessed in a spectrum of lung cancer mouse models, with a goal of advancing a lead molecule into clinical development for the treatment of metastatic lung cancer.